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Download fileSubstrate Stiffness-Dependent Carbon Nanotube-Induced Lung Fibrogenesis
journal contribution
posted on 2019-08-05, 17:35 authored by Kai Wang, Lin Shi, Will Linthicum, Kun Man, Xiaoqing He, Qi Wen, Liying Wang Rojanasakul, Yon Rojanasakul, Yong YangMost living tissues exhibit the specific
stiffness, which has been
known to have profound influence on cell behaviors, yet how the stiffness
affects cellular responses to engineered nanomaterials has not been
elucidated. Particularly, discrepancies exist between in vitro and in vivo nanotoxicological studies. Here, we
investigated the effects of substrate stiffness on the fibrogenic
responses of normal human lung fibroblasts (NHLFs) to multiwalled
carbon nanotubes (MWCNTs). NHLFs were grown on polyacrylamide (PAAm)
hydrogels with the stiffness comparable to that of human normal and
fibrotic lung tissues, and treated with MWCNTs for various time. The
fibrogenic responses, including cell proliferation, reactive oxygen
species production, and collagen I expression, of NHLFs to MWCNTs
were observed to be regulated by substrate stiffness in a time-dependent
manner. NHLFs generally were rounded on soft hydrogels and required
a long treatment time to exhibit fibrogenic responses, while on stiff
hydrogels the cells were well-spread with defined stress fibers and
short-time MWCNTs treatment sufficiently induced the fibrogenic responses.
Mechanistic studies showed that MWCNTs induced fibrogenesis of NHLFs
through promoting expression and phosphorylation of focal adhesion
kinase (FAK), while attenuating intracellular tension in the cells
on stiff gels could increase MWCNTs uptake and thus elevate the induced
fibrogenic responses. Moreover, we proposed a time-stiffness superposition
principle to describe the equivalent effects of treatment time and
substrate stiffness on nanomaterials-induced fibrogenesis, which suggested
that increasing substrate stiffness expedited fibrogenesis and shed
light on the rational design of in vitro models for
nanotoxicological study.
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Keywords
MWCNTtime-stiffness superposition principleattenuating intracellular tensionfibrogenesiexhibit fibrogenic responsesfibrotic lung tissuesmultiwalled carbon nanotubestreatment timeSubstrate Stiffness-Dependent Carbon Nanotube-Induced Lung Fibrogenesisvivo nanotoxicological studiesreactive oxygen species productionfibrogenic responsesNHLFhydrogelFAKsubstrate stiffness